Multisubstituted pyrimidines effectively inhibit bacterial growth and biofilm formation of Staphylococcus aureus

Abstract

Biofilms are multicellular communities of microorganisms that generally attach to surfaces in a self-produced matrix. Unlike planktonic cells, biofilms can withstand conventional antibiotics, causing significant challenges in the healthcare system. Currently, new chemical entities are urgently needed to develop novel anti-biofilm agents. In this study, we designed and synthesized a set of 2,4,5,6-tetrasubstituted pyrimidines and assessed their antibacterial activity against planktonic cells and biofilms formed by Staphylococcus aureus. Compounds 9e, 10d, and 10e displayed potent activity for inhibiting the onset of biofilm formation as well as for killing pre-formed biofilms of S. aureus ATCC 25923 and Newman strains, with half-maximal inhibitory concentration (IC50) values ranging from 11.6 to 62.0 µM. These pyrimidines, at 100 µM, not only decreased the number of viable bacteria within the pre-formed biofilm by 2–3 log10 but also reduced the amount of total biomass by 30–50%. Furthermore, these compounds were effective against planktonic cells with minimum inhibitory concentration (MIC) values lower than 60 µM for both staphylococcal strains. Compound 10d inhibited the growth of S. aureus ATCC 25923 in a concentration-dependent manner and displayed a bactericidal anti-staphylococcal activity. Taken together, our study highlights the value of multisubstituted pyrimidines to develop novel anti-biofilm agents.

Synthetic Antibacterial Quaternary Phosphorus Salts Promote Methicillin-Resistant Staphylococcus aureus-Infected Wound Healing

“…34 Moreover, the XRD patterns suggested a crystalline phase (Figure S1C). As shown in Figure S2, 1 To measure the antibacterial activity of the quaternary phosphorus salts, four bacterial strains (S. aureus, MRSA, E. coli, and P. aeruginosa) were treated with the salts and their inhibition zone and MIC were evaluated. The agar diffusion assay showed that PA is insensitive to (1,2-DBTPP)Br 2 , (1,4-DBTPP)Br 2 , and (1,6-DBTPP)Br 2 ; however, the presence of a clear zone surrounding the well appeared where these three materials were introduced (Figure S3).…”

“…(1,4-DBTPP)Br 2 showed better antimicrobial efficiency against MRSA than (1,2-DBTPP)Br 2 and (1,6-DBTPP)Br 2 . Therefore, we focused on the antibacterial effect of only (1,4-DBTPP)Br 2 against MRSA in subsequent experiments.…”

“…This number is expected to increase to 10 million deaths by 2050, resulting in an economic loss of approximately 100 trillion USD. 1 Unfortunately, the development of novel antibiotics is challenging owing to the rapid emergence of resistant microorganisms. In addition, the development of novel antibacterial agents requires significant economic, time investments, as well as labor supply.…”

Repurposing the Sphingosine-1-Phosphate Receptor Modulator Etrasimod as an Antibacterial Agent Against Gram-Positive Bacteria

“…Bacterial biofilms are highly tolerant to host immune system and can be up to 1,000 times less sensitive to antibiotic treatment than bacteria in planktonic/single cell state ( Kumar et al, 2017 ). Therefore, it is necessary to find agents that are not only active against planktonic cells, but also able to act on biofilms, either by preventing their formation or by disrupting them ( Hansa et al, 2021 ; Provenzani et al, 2021 ). However, conventional discovery of antibiotics is a long and expensive process, with a low success rate, and has not been able to cope with the emergence of antibiotic resistance and tolerance ( Payne et al, 2007 ; Ribeiro da Cunha et al, 2019 ).…”

Exploring Anticandidal and Antibiofilm Potentials of Synthesized N-(Substitutedbenzylidene)-4,6-Dimethoxypyrimidin-2-Amine Analogues

“…23 On the other hand, pyrimidine nitrogen-containing heterocyclic compounds are of great significance as they are abundant in nature and a wide spectrum of biological activities exhibited by the synthetic/semisynthetic derivatives. 24,25 Pyrimidine derivatives have shown a wide spectrum of biological activities such as antifungal (f-h), [24][25][26][27] antibiofilm (f-h), 25,26 antibacterial (a-e), 27 antiviral (j-k) 28 and anticancer (l-m). 29 Fig.…”